Authors describe 2 cases of likely iatrogenic cerebral amyloid angiopathy after cadaveric dura mater use for cardiac surgery during infancy. Both are remarkable for their early age at onset, lack of genetic risk factor, and demonstration of brain amyloidosis.
To alert on the risk of interhuman transmission of β-amyloid (Aβ) pathology leading to cerebral amyloid angiopathy (CAA) after non-neurosurgical procedures, here cardiovascular procedures, using cadaveric dura mater (DM) patches.
Millions of neurons branch throughout our bodies, keeping them in close communication with our brains. This peripheral network begins to take shape long before birth, as the cells of a growing embryo move into position and adopt their specialized roles. This crucial stage of human development can’t be monitored directly, but by examining genetic clues that linger in adult cells, scientists have now gained surprising insights into the developmental origins of the peripheral nervous system.
Researchers led by Xiaoxu Yang, Ph.D., at University of Utah Health, and Keng Ioi Vong, Ph.D., and Joseph Gleeson, M.D., at the University of California San Diego, have discovered that within the first few weeks of development, some of an embryo’s cells have already been selected to take on particular roles in the peripheral nervous system. Their findings, recently reported in the journal Nature, overturn longstanding assumptions in biology.
Their discovery could change the way scientists think about treatments for a variety of childhood diseases that begin in the cells of the peripheral nervous system.
A new study challenges the long-standing view that Alzheimer’s is driven primarily by amyloid plaques, instead pointing to a subtle but critical competition inside neurons.
New research led by the University of California, Riverside, suggests Alzheimer’s disease may not be driven solely by plaque buildup in the brain, as widely believed. Instead, it may result from one protein disrupting the normal function of another.
For years, scientists have focused on amyloid beta (a-beta) as the main cause of Alzheimer’s. Clusters of this protein are commonly found in patients, and genetic mutations that raise a-beta levels are known to trigger early-onset Alzheimer’s.
Scientists have taken an important step toward a gene therapy that could one day turn off the extra genetic material that causes Down syndrome (DS). Down syndrome is a genetic condition caused by an extra chromosome 21 (and consequently hundreds of triplicate genes) that leads to developmental and neurological issues. According to the Washington-based National Down Syndrome Society, approximately 1 in every 640 babies in the United States is born with DS. That makes it the most common chromosomal condition.
Traditional gene therapy targets one or two genes, but in this approach, scientists at Beth Israel Deaconess Medical Center and Harvard Medical School found a way to silence much of the extra chromosome’s activity in the cell at once.
Details of their research are published in a paper in the journal Proceedings of the National Academy of Sciences.
After receiving a stem cell transplant from his brother, a 63-year-old Norwegian man known as the “Oslo patient” has become one of only a handful of people to see their HIV (human immunodeficiency virus) go into long-term remission.
While HIV can now be controlled with medication that stops the virus from replicating, the virus remains in the body, rebounding when the drugs are stopped. So case studies like this one are invaluable for researchers working towards a full cure.
The Oslo man was given a bone marrow stem cell transplant to treat a rare type of blood cancer. Discovering at the last minute that his brother carried a rare genetic mutation previously shown to resist HIV, researchers led by a team from Oslo University Hospital closely tracked the operation’s impact on the virus.
Scientists at the Buck Institute for Research on Aging, along with collaborators at UC San Francisco, have discovered that APOE4, the most common genetic risk factor for Alzheimer’s disease, causes bone quality deficits specifically in female mice, through a mechanism that is invisible to standard imaging and can emerge as early as midlife. The findings, published in Advanced Science, reveal an unexpected biological link between Alzheimer’s risk and skeletal health, and identify a new molecular pathway that could one day inform earlier diagnosis of cognitive decline or guide treatment for bone quality loss in women who carry the APOE4 gene.
“What makes this finding so striking is that bone quality is being compromised at a molecular level that a standard bone scan simply will not catch,” says Buck professor Birgit Schilling, Ph.D., a senior author of the study. “APOE4 is quietly disrupting the very cells responsible for keeping bone strong, and it is doing this specifically in females, which mirrors what we see with Alzheimer’s disease risk.”
Physicians have long observed that people with Alzheimer’s disease suffer bone fractures at higher rates, and that a diagnosis of osteoporosis in women is actually the earliest known predictor of Alzheimer’s. But the underlying mechanism connecting brain and bone health has remained elusive.
A research team has discovered an enhanced CRISPR gene-editing system that could enable targeted delivery inside the human body—a key step toward broader clinical use. Researchers identified a naturally occurring enzyme, Al3Cas12f, that is small enough to fit into adeno-associated virus vectors, a leading targeted delivery method for gene therapies. They then engineered an enhanced version that dramatically improved gene-editing performance in human cells.
The advance addresses a major limitation in CRISPR technology. Commonly used gene-editing proteins are too large for targeted delivery systems, restricting clinical applications to cells modified outside the body, such as blood and bone marrow.
“Smart delivery of gene editing systems is a powerful notion with broad clinical implications, and this basic science finding takes us a significant step toward that future,” said Erica Brown, Ph.D., acting director of NIH’s National Institute of General Medical Sciences (NIGMS).
This study describes a novel ATXN2 expansion within the classic pathogenic range for spinocerebellar ataxia 2 that manifests as an early-onset neurodegenerative disorder in the homozygous state, while being asymptomatic into late adulthood in the heterozygous state.
The length and content of ATXN2 trinucleotide repeat significantly influences disease development and clinical phenotype. ATXN2 alleles containing 13–31 CAG trinucleotide repeats are normal and commonly found in healthy individuals4 and over 90% of tested individuals possess an allele containing 22 CAG repeats.21 Spinocerebellar ataxia type 2 is caused by dominant alleles of 33 or more CAG trinucleotide repeats.11,22 Alleles containing 33–34 CAG repeats are considered reduced penetrance alleles, and carriers may or may not develop late onset ataxia.22 Fully penetrant alleles most commonly have 37–39 CAG repeats and are pathogenic for SCA2.11 While SCA2 alleles of 31 pure CAG repeats exhibit high instability on inheritance, it has been proposed that CAA interruptions confers meiotic stability.23 An anticipation phenomenon in SCA2 has also been described, consisting of earlier disease onset and increased clinical severity in subsequent generations which are mirrored by an increase in CAG repeat size.12 Patients with SCA2-related parkinsonism carry intermediate range alleles and possess alleles with CAA interruptions.24,25 Similarly, ATNX2 variants associated with ALS are CAA interrupted and are rarely in the pathogenic range of SCA2.26,27 Contrasting with trinucleotide expansion diseases, repeat size has no bearing on ALS AO but correlates with disease risk.28 ATXN2 has been identified as a disease modifier gene for a variety of neurologic conditions and similarly, various genes may influence the AO of SCA2, including long normal repeats in the CACNA1A and RAI1 genes.29 Nonetheless, the most important predictor of AO and clinical severity remains the polyglutamine repeat expansion size.30
Infantile and childhood forms of SCA2 are described, and these patients present with a multi-systematic neurodegenerative disorder including developmental delay, retinitis pigmentosa, optic atrophy, hypotonia, seizures, facial dysmorphism, dystonic features, and early mortality.21,31 Infantile cases all possess extreme length CAG repeats (range 69–884) in the heterozygous state, with clinical severity related to repeat size, and inherited with an anticipation phenomenon from parents within the fully penetrant range of SCA2 (range 39–47 CAG repeats).21,31
Homozygous cases of SCA2 are exceedingly rare.32,33 Notably, a patient with 31/31 CAG alleles developed late-onset cerebellar ataxia, suggesting that patients with homozygous variants may manifest signs of disease within a nonpathogenic variant range, that is not associated with disease development in the heterozygous state.18,32 Two homozygous cases from an Indian family with 35/37 and 36/39 CAG repeats alleles developed early onset, levodopa responsive Parkinson disease without ataxia,33 while several family members with heterozygous ATXN2 variants exhibited parkinsonism and/or ataxia with variable ages of onset ranging from adulthood to their sixties.33 Moreover, two homozygous cases with intermediate alleles of 32/3217 and 33/3327 displayed a pure ALS phenotype, without ataxia. These cases highlight the phenotypical variability of homozygous ATXN2 variants.